Method for the administration of an anticholinergic by inhalation

ABSTRACT

An inhalation kit comprising: (a) an inhaler displaying a flow resistance of about 0.01 to 0.1, √{square root over (kPa)} min/L; and (b) an inhalable powder comprising tiotropium in admixture with a physiologically acceptable excipient with an average particle size of between 10 to 500 μm, and a method of administering an inhalable powder containing tiotropium in admixture with a physiologically acceptable excipient with an average particle size of between 10 pm to 500 μm, the method comprising actuating an inhaler a flow resistance of about 0.01 to 0.1 √{square root over (kPa)} min/L containing the inhalable powder.

RELATED APPLICATION

This application claims benefit of U.S. Ser. No. 60/386,794, filed Jun.7, 2002.

FIELD OF THE INVENTION

The invention relates to a method for the administration of powderedpreparations containing tiotropium by inhalation.

BACKGROUND OF THE INVENTION

Tiotropium bromide is known from European Patent Application EP 418 716

A1 and has the following chemical structure:

Tiotropium bromide is a highly effective anticholinergic with along-lasting activity which can be used to treat respiratory complaints,particularly chronic obstructive pulmonary disease (COPD) and asthma.The term tiotropium refers to the free ammonium cation.

For treating the abovementioned complaints, it is useful to administerthe active substance by inhalation. In addition to the administration ofbroncholytically active compounds in the form of metered aerosols andinhalable solutions, the use of inhalable powders containing activesubstance is of particular importance.

With active substances which have a particularly high efficacy, onlysmall amounts of the active substance are needed per single dose toachieve the desired therapeutic effect. In such cases, the activesubstance has to be diluted with suitable excipients in order to preparethe inhalable powder. Because of the large amount of excipient, theproperties of the inhalable powder are critically influenced by thechoice of excipient. When choosing the excipient, its particle size isparticularly important. As a rule, the finer the excipient, the poorerits flow properties. However, good flow properties are a prerequisitefor highly accurate metering when packing and dividing up the individualdoses of preparation, e.g., when producing capsules for powderinhalation or when the patient is metering the individual dose beforeusing a multi-dose inhaler. It has also been found that the particlesize of the excipient has a considerable influence on the proportion ofactive substance in the inhalable powder which is delivered forinhalation. The term inhalable proportion of active substance refers tothe particles of the inhalable powder which are conveyed deep into thebranches of the lungs when inhaled with a breath. The particle sizerequired for this is between 1 μm and 10 μm, preferably less than 5 μm.

Finally, it has been found that the intended therapeutic effect upon theadministration of a pharmaceutical composition via inhalation can bedecisively influenced by the inhalation device.

Accordingly, the aim of the invention is to provide for atherapeutically efficient method for the administration of inhalablepowders containing tiotropium. Another object of the invention is toprovide for an inhalation kit comprising a tiotropium containing powderand an inhalation device, the kit being applicable in the method foradministration mentioned before.

Inhalation devices are known for use with blister packs in which themedicament is held in powder form in the blisters thereof. Such devicesinclude a puncturing member which punctures each blister in turn, thusenabling the medicament to be inhaled therefrom.

It is an object of the present invention to provide an inhalation devicethe design of which has the potential, if desired, to handle amedicament pack having a large number of discrete unit doses, withoutthe device becoming unacceptably large.

The invention also provides a medicament pack for use in an inhalationdevice, the pack comprising an elongate strip formed from a base sheethaving a plurality of recesses spaced along its length and a lid sheethermetically but peelably sealed thereto to define a plurality ofcontainers, each container having therein inhalable medicament in powderform. The strip is preferably sufficiently flexible to be wound into aroll.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an exploded view of a first inhaler of the invention;

FIG. 2 is a rear view of a second embodiment of the invention;

FIG. 3 is an axonometric exploded view of the components of theembodiment of FIG. 2.

FIGS. 4 a and 4 b are an axial section and cross-section respectively,on a larger scale than FIGS. 2 and 3, of a mouthpiece which may be usedin the second embodiment (or in some other embodiment);

FIG. 5 is a front view of a third powder inhaler device according to theinvention, with a cover thereof removed to show the interior;

FIG. 6 is an axonometric exploded view of the embodiment of FIG. 5;

FIG. 7 is a front view of a fourth embodiment, showing the interiorstructure thereof;

FIG. 8 is an axial view, on a larger scale, showing the mouthpiece ofthe embodiment of FIG. 7;

FIGS. 9 to 12 show a fifth embodiment of the invention, FIG. 9 being anunderplan view, FIG. 10 a section on line A-A in FIG. 9, FIG. 11 asection on line B-B in FIG. 9, and FIG. 12 an exploded view on a smallerscale;

FIGS. 12 a to 12 d show the fifth embodiment in successive stages ofoperation, and FIG. 12 e is a section taken on line A-A in FIG. 12 a;

FIG. 13 is a perspective view on a larger scale showing an embodiment ofa medicament pack according to the invention.

FIG. 14 is an exploded perspective view of sixth device according to oneembodiment of the invention;

FIG. 15 is a detailed view of a plunger device of the device shown inFIG. 14;

FIG. 16 is an elevation of a seventh embodiment of the invention;

FIG. 17 is an exploded view of the embodiment illustrated in FIG. 16.

DETAILED DESCRIPTION OF THE INVENTION

In the method according to the invention an inhalable powder containingtiotropium, preferably in an amount of 0.001% to 5%, in admixture with aphysiologically acceptable excipient is administered.

Of particular interest for the method according to the invention is aninhalable powder containing 0.01% to 2%, preferably 0.04% to 0.8%, morepreferably 0.08% to 0.64% tiotropium in admixture with a physiologicallyacceptable excipient is administered.

More preferably in the method according to the invention an inhalablepowder containing 0.1% to 0.4% tiotropium in admixture with aphysiologically acceptable excipient is administered.

By tiotropium is meant the free ammonium cation. The counter-ion (anion)may be chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate,or methylsulfate. Of these anions, the bromide is preferred.

Accordingly, the method according to the present invention preferablyrelates to inhalable powders which contain tiotropium in form oftiotropium bromide in an amount of 0.0012% to 6.02%, in admixture with aphysiologically acceptable excipient. Of particular interest for themethod according to the invention is an inhalable powder containing0.012% to 2.41%, preferably 0.048% to 0.96%, more preferably 0.096% to0.77%, tiotropium bromide in admixture with a physiologically acceptableexcipient is administered.

More preferably in the method according to the invention an inhalablepowder containing 0.12% to 0.48% tiotropium bromide in admixture with aphysiologically acceptable excipient is administered.

Tiotropium bromide is, depending on the choice of reaction conditionsand solvents, obtainable in different crystalline modifications. Mostpreferred according to the invention are those powder preparations, thatcontain tiotropium in form of the crystalline tiotropium bromidemonohydrate. Accordingly, the powdered preparations obtainable accordingto the invention preferably contain 0.0012% to 6.25% crystallinetiotropium bromide monohydrate in admixture with a physiologicallyacceptable excipient is administered. Of particular interest for themethod according to the invention is an inhalable powder containing0.0125% to 2.5%, preferably 0.05% to 1%, more preferably 0.1% to 0.8%,crystalline tiotropium bromide monohydrate in admixture with aphysiologically acceptable excipient is administered.

More preferably in the method according to the invention an inhalablepowder containing 0.12% to 0.5% crystalline tiotropium bromidemonohydrate in admixture with a physiologically acceptable excipient isadministered.

Examples of physiologically acceptable excipients which may be used toprepare the inhalable powders applicable according to the inventioninclude, for example, monosaccharides (e.g., glucose or arabinose),disaccharides (e.g., lactose, saccharose, or maltose), oligo- andpolysaccharides (e.g., dextrane), polyalcohols (e.g., sorbitol,mannitol, or xylitol), salts (e.g., sodium chloride or calciumcarbonate) or mixtures of these excipients with one another. Preferably,mono- or disaccharides are used, while the use of lactose or glucose ispreferred, particularly, but not exclusively, in the form of theirhydrates, preferably in the form of their monohydrates.

In the method according to the invention, the average particle size ofthe physiologically acceptable excipient is preferably between 10 μm to500 μm, more preferably between 15 μm to 200 μm, most preferably between20 μm to 100 μm. If not otherwise emphasized, the term average particlesize according to the invention is to be understood as the Mass MedianAerodynamic Diameter (MMAD). Methods for the determination thereof areknown in the art.

Besides the coarser particle fraction of the excipient mentionedhereinbefore, the excipient can optionally additionally contain aspecifically added fraction of excipient of finer particle size. Thisfiner particle size fraction is characterized by an average particlesize of 1 μm to 9 μm, preferably 2 μm to 8 μm, more preferably 3 μm to 7μm.

If a finer particle fraction is present, the proportion of finerexcipient in the total amount of excipient is 1% to 20%, preferably 3%to 15%, more preferably 5% to 10%. When reference is made to a mixturewithin the scope of the present invention, this always means a mixtureobtained by mixing together clearly defined components. Accordingly,when an excipient mixture of coarser and finer excipients is mentioned,this can only denote mixtures obtained by mixing a coarser excipientcomponent with a finer excipient component.

The percentages given within the scope of the present invention arealways percent by weight.

In the method according to the invention, the inhalable powdersmentioned hereinbefore may efficiently be administered using inhalersthat are characterized by a specific flow resistance (R).

The flow resistance of inhalers can be calculated via the followingformula:

$v = {\frac{1}{R} \cdot \sqrt{p}}$

wherein: v is the volumetric flow rate (L/min);

p is the pressure drop (kPa); and

R is the flow resistance.

In the method according to the invention, the flow resistance Rcharacterizing the inhaler is in a range of about 0.01 to 0.1 √{squareroot over (kPa)} min/L preferably in the range of about 0.02 to 0.06√{square root over (kPa)} min/L.

Accordingly, the invention relates to a method for the administration ofan inhalable powder containing tiotropium, preferably in an amount of0.001% to 5%, in admixture with a physiologically acceptable excipientwith an average particle size of between 10 μm to 500 μm, and furthercharacterized in that the tiotropium containing powder is administeredby an inhaler displaying a flow resistance of about 0.01 to 0.1 √{squareroot over (kPa)} min/L.

In another embodiment, the invention relates to a method for thetreatment of airway diseases, particularly chronic obstructive pulmonarydisease (COPD) and asthma, characterized in that an inhalable powdercontaining tiotropium, preferably in an amount of 0.001% to 5%, inadmixture with a physiologically acceptable excipient with an averageparticle size of between 10 μm to 500 μm, is administered via inhalationby an inhaler displaying a flow resistance of about 0.01 to 0.1 √{squareroot over (kPa)} min/L.

In another embodiment, the invention relates to the use of an inhalerfor the administration of a tiotropium containing inhalable powder viainhalation, characterized in that the inhalable powder containstiotropium, preferably in an amount of 0.001% to 5%, in admixture with aphysiologically acceptable excipient with an average particle size ofbetween 10 μm to 500 μm, and further characterized in that the inhalerdisplays a flow resistance of about 0.01 to 0.1 √{square root over(kPa)} min/L.

In yet another embodiment the invention relates to an inhalation kitconsisting of an inhaler displaying a flow resistance of about 0.01 to0.1 √{square root over (kPa)} min/L and an inhalable powder containingtiotropium, preferably in an amount of 0.001% to 5%, in admixture with aphysiologically acceptable excipient with an average particle size ofbetween 10 μm to 500 μm.

In another preferred embodiment according to the invention, the inhalerdescribed in FIG. 1 is applied. For the administration of tiotropiumcontaining powders by inhalation by means of the inhaler according toFIG. 1, it is required to fill appropriate amounts of the powder intocapsules. Methods for filling powders into capsules are known in theart.

The inhaler according to FIG. 1 is characterized by a housing 1containing two windows 2, a deck 3 in which there are air inlet portsand which is provided with a screen 5 secured via a screen housing 4, aninhalation chamber 6 connected to the deck 3 on which there is a pushbutton 9 provided with two sharpened pins 7 and movable counter to aspring 8, a mouthpiece 12 which is connected to the housing 1, the deck3 and a cover 11 via a spindle 10 to enable it to be flipped open orshut and three holes 13 with diameters below 1 mm in the central regionaround the capsule chamber 6 and underneath the screen housing 4 andscreen 5.

The main air flow enters the inhaler between deck 3 and base 1 near tothe hinge. The deck has in this range a reduced width, which forms theentrance slit for the air. Then the flow reverses and enters the capsulechamber 6 through the inlet tube. The flow is then further conductedthrough the filter and filter holder to the mouthpiece. A small portionof the flow enters the device between mouthpiece and deck and flows thenbetween filter holder and deck into the main stream. Due to productiontolerances, there is some uncertainty in this flow because of the actualwidth of the slit between filter holder and deck. In case of new orreworked tools, the flow resistance of the inhaler may therefore be alittle off the target value. To correct this deviation, the deck has inthe central region around the capsule chamber 6 and underneath thescreen housing 4 and screen 5 three holes 13 with diameters below 1 mm.Through these holes 13 flows air from the base into the main air streamand reduces such slightly the flow resistance of the inhaler. The actualdiameter of these holes 13 can be chosen by proper inserts in the toolsso that the mean flow resistance can be made equal to the target value.

Accordingly, in a preferred embodiment the invention relates to a methodfor the administration of an inhalable powder containing tiotropium,preferably in an amount of 0.001% to 5%, in admixture with aphysiologically acceptable excipient with an average particle size ofbetween 10 μm to 500 μm, by means of the inhaler according to FIG. 1,comprising a housing, containing two windows, a deck in which there areair inlet ports and which is provided with a screen secured via a screenhousing, an inhalation chamber connected to the deck on which there is apush button provided with two sharpened pins and movable counter to aspring, a mouthpiece which is connected to the housing, the deck and acover via a spindle to enable it to be flipped open or shut, and threeholes with diameters below 1 mm in the central region around the capsulechamber and underneath the screen housing and screen.

In another embodiment, the invention relates to a method for treatmentof airway diseases, particularly chronic obstructive pulmonary diseaseand asthma, characterized in that an inhalable powder containingtiotropium, preferably in an amount of 0.001% to 5%, in admixture with aphysiologically acceptable excipient with an average particle size ofbetween 10 μm to 500 μm, is administered via inhalation by the inhaleraccording to FIG. 1, comprising a housing, containing two windows, adeck in which there are air inlet ports and which is provided with ascreen secured via a screen housing, an inhalation chamber connected tothe deck on which there is a push button provided with two sharpenedpins and movable counter to a spring, a mouthpiece which is connected tothe housing, the deck and a cover via a spindle to enable it to beflipped open or shut, and three holes with diameters below 1 mm in thecentral region around the capsule chamber and underneath the screenhousing and screen.

In another preferred embodiment, the invention relates to the use of theinhaler according to FIG. 1, comprising a housing, containing twowindows, a deck in which there are air inlet ports and which is providedwith a screen secured via a screen housing, an inhalation chamberconnected to the deck on which there is a push button provided with twosharpened pins and movable counter to a spring, a mouthpiece which isconnected to the housing, the deck and a cover via a spindle to enableit to be flipped open or shut, and three holes with diameters below 1 mmin the central region around the capsule chamber and underneath thescreen housing and screen, for the administration of an inhalablepowdered containing tiotropium, preferably in an amount of 0.001% to 5%,in admixture with a physiologically acceptable excipient with an averageparticle size of between 10 μm to 500 μm.

In yet another preferred embodiment, the invention relates to aninhalation kit consisting of an inhalable powdered containingtiotropium, preferably in an amount of 0.001% to 5%, in admixture with aphysiologically acceptable excipient with an average particle size ofbetween 10 μm to 500 μm, and the inhaler according to FIG. 1, comprisinga housing, containing two windows, a deck in which there are air inletports and which is provided with a screen secured via a screen housing,an inhalation chamber connected to the deck on which there is a pushbutton provided with two sharpened pins and movable counter to a spring,a mouthpiece which is connected to the housing, the deck and a cover viaa spindle to enable it to be flipped open or shut, and three holes withdiameters below 1 mm in the central region around the capsule chamberand underneath the screen housing and screen.

In another preferred embodiment according to the invention the inhaleraccording to U.S. Pat. No. 4,524,769 is applied. This inhaler (orinhalator) is activated by the air flow generated at inhalation. Thedisclosure of U.S. Pat. No. 4,524,769 is incorporated herein byreference in its entirety.

Accordingly, in a preferred embodiment, the invention relates to amethod for the administration of an inhalable powder containingtiotropium, preferably in an amount of 0.001% to 5%, in admixture with aphysiologically acceptable excipient with an average particle size ofbetween 10 μm to 500 μm, by means of the inhaler according to U.S. Pat.No. 4,524,769, comprising a nozzle, a conduit connected to the nozzle, astorage chamber adjacent the conduit for storing the inhalable powder tobe dispensed by the inhalator, a perforated membrane having a pluralityof preselected perforated portions each holding and dispensing areproducible unit dose of less than 50 mg of the inhalable powder, themembrane being mounted for movement between the conduit and the storagechamber so that one of the preselected portions is positioned across theconduit whereby the active compound held in the perforation thereof canbe dispensed into the conduit and another of the preselected portionsthereof is disposed within the storage chamber, dose loading means forintroducing the inhalable powder in the storage chamber into theperforation of the preselected portion of the membrane disposed withinthe storage chamber, and maneuvering means for displacing the perforatedmembrane through a plurality of positions whereby successive preselectedportions of the perforated membrane holding the inhalable powder arepositioned across the conduit for dispensing the inhalable powder. Thisdosage inhalator is suitable for dispensing to a patient a micronizedsolid, pharmacologically active compound in dry powdered form having aparticle size of less than 5 micrometers suspended in a gas.

In another embodiment, the invention relates to a method for treatmentof airway diseases, particularly chronic obstructive pulmonary diseaseand asthma, characterized in that an inhalable powder containingtiotropium, preferably in an amount of 0.001% to 5%, in admixture with aphysiologically acceptable excipient with an average particle size ofbetween 10 μm to 500 μm, is administered via inhalation by the inhaleraccording to U.S. Pat. No. 4,524,769, comprising a nozzle, a conduitconnected to the nozzle, a storage chamber adjacent the conduit forstoring the inhalable powder to be dispensed by the inhalator, aperforated membrane having a plurality of preselected perforatedportions each holding and dispensing a reproducible unit dose of lessthan 50 mg of the inhalable powder, the membrane being mounted formovement between the conduit and the storage chamber so that one of thepreselected portions is positioned across the conduit whereby the activecompound held in the perforation thereof can be dispensed into theconduit and another of the preselected portions thereof is disposedwithin the storage chamber, dose loading means for introducing theinhalable powder in the storage chamber into the perforation of thepreselected portion of the membrane disposed within the storage chamber,and maneuvering means for displacing the perforated membrane through aplurality of positions whereby successive preselected portions of theperforated membrane holding the inhalable powder are positioned acrossthe conduit for dispensing the inhalable powder.

In another preferred embodiment, the invention relates to the use of theinhaler according to U.S. Pat. No. 4,524,769 comprising a nozzle, aconduit connected to the nozzle, a storage chamber adjacent the conduitfor storing the inhalable powder to be dispensed by the inhalator, aperforated membrane having a plurality of preselected perforatedportions each holding and dispensing a reproducible unit dose of lessthan 50 mg of the inhalable powder, the membrane being mounted formovement between the conduit and the storage chamber so that one of thepreselected portions is positioned across the conduit whereby the activecompound held in the perforation thereof can be dispensed into theconduit and another of the preselected portions thereof is disposedwithin the storage chamber, dose loading means for introducing theinhalable powder in the storage chamber into the perforation of thepreselected portion of the membrane disposed within the storage chamber,and maneuvering means for displacing the perforated membrane through aplurality of positions whereby successive preselected portions of theperforated membrane holding the inhalable powder are positioned acrossthe conduit for dispensing the inhalable powder, for the administrationof an inhalable powdered containing tiotropium, preferably in an amountof 0.001% to 5%, in admixture with a physiologically acceptableexcipient with an average particle size of between 10 μm to 500 μm.

In yet another preferred embodiment, the invention relates to aninhalation kit consisting of an inhalable powdered containingtiotropium, preferably in an amount of 0.001% to 5%, in admixture with aphysiologically acceptable excipient with an average particle size ofbetween 10 μm to 500 μm, and the inhaler according to U.S. Pat. No.4,524,769, comprising a nozzle, a conduit connected to the nozzle, astorage chamber adjacent the conduit for storing the inhalable powder tobe dispensed by the inhalator, a perforated membrane having a pluralityof preselected perforated portions each holding and dispensing areproducible unit dose of less than 50 mg of the inhalable powder, themembrane being mounted for movement between the conduit and the storagechamber so that one of the preselected portions is positioned across theconduit whereby the active compound held in the perforation thereof canbe dispensed into the conduit and another of the preselected portionsthereof is disposed within the storage chamber, dose loading means forintroducing the inhalable powder in the storage chamber into theperforation of the preselected portion of the membrane disposed withinthe storage chamber, and maneuvering means for displacing the perforatedmembrane through a plurality of positions whereby successive preselectedportions of the perforated membrane holding the inhalable powder arepositioned across the conduit for dispensing the inhalable powder.

Among compound groups and specific compounds which are suitable foradministering with a powder inhalator according to the present inventionthe following can be mentioned:

betareceptor stimulating agents such as adrenaline, isoprenaline,orciprenaline, salbutamol and terbutaline,

steroids for inhalation such as budesonide, and

substances intended for nasal administration.

Especially useful are terbutaline and budesonide.

The active compound can be administered in micronized form withoutadditional ingredients or in pharmaceutically modified micronized formin order to obtain improved flow properties. The micronized particlesmay be covered with a film functioning for example by masking bittertaste of the active compound, or by providing slow release of the activecompound in the respiratory tract.

In another preferred embodiment according to the invention, the inhaleraccording to U.S. Pat. No. 5,590,645 is applied. The disclosure of U.S.Pat. No. 5,590,645 is incorporated herein by reference in its entirety.

Accordingly, in a preferred embodiment, the invention relates to amethod for the administration of an inhalable powder containingtiotropium, preferably in an amount of 0.001% to 5%, in admixture with aphysiologically acceptable excipient with an average particle size ofbetween 10 μm to 500 μm, by means of the inhaler according to U.S. Pat.No. 5,590,645, comprising a medicament pack having a plurality ofcontainers for containing medicament in powder form wherein thecontainers are spaced along the length of and defined between twopeelable sheets secured to each other, an opening station for receivinga container of the medicament pack being, means positioned to engagepeelable sheets of a container which has been received in the openingstation for peeling apart the peelable sheets, to open such a container,an outlet, positioned to be in communication with an opened container,through which a user can inhale medicament in powder form from such anopened container, and indexing means for indexing in communication withthe outlet containers of a medicament pack in use with the inhalationdevice.

In another embodiment, the invention relates to a method for treatmentof airway diseases, particularly chronic obstructive pulmonary diseaseand asthma, characterized in that an inhalable powder containingtiotropium, preferably in an amount of 0.001% to 5%, in admixture with aphysiologically acceptable excipient with an average particle size ofbetween 10 μm to 500 μm, is administered via inhalation by the inhaleraccording to U.S. Pat. No. 5,590,645, comprising a medicament packhaving a plurality of containers for containing medicament in powderform wherein the containers are spaced along the length of and definedbetween two peelable sheets secured to each other, an opening stationfor receiving a container of the medicament pack being, means positionedto engage peelable sheets of a container which has been received in theopening station for peeling apart the peelable sheets, to open such acontainer, an outlet, positioned to be in communication with an openedcontainer, through which a user can inhale medicament in powder formfrom such an opened container, and indexing means for indexing incommunication with the outlet containers of a medicament pack in usewith the inhalation device.

In another preferred embodiment, the invention relates to the use of theinhaler according to U.S. Pat. No. 5,590,645, comprising a medicamentpack having a plurality of containers for containing medicament inpowder form wherein the containers are spaced along the length of anddefined between two peelable sheets secured to each other, an openingstation for receiving a container of the medicament pack being, meanspositioned to engage peelable sheets of a container which has beenreceived in the opening station for peeling apart the peelable sheets,to open such a container, an outlet, positioned to be in communicationwith an opened container, through which a user can inhale medicament inpowder form from such an opened container, and indexing means forindexing in communication with the outlet containers of a medicamentpack in use with the inhalation device, for the administration of aninhalable powdered containing tiotropium, preferably in an amount of0.001% to 5%, in admixture with a physiologically acceptable excipientwith an average particle size of between 10 μm to 500 μm.

In yet another preferred embodiment, the invention relates to aninhalation kit consisting of an inhalable powdered containingtiotropium, preferably in an amount of 0.001% to 5%, in admixture with aphysiologically acceptable excipient with an average particle size ofbetween 10 μm to 500 μm, and the inhaler according to U.S. Pat. No.5,590,645, comprising a medicament pack having a plurality of containersfor containing medicament in powder form wherein the containers arespaced along the length of and defined between two peelable sheetssecured to each other, an opening station for receiving a container ofthe medicament pack being, means positioned to engage peelable sheets ofa container which has been received in the opening station for peelingapart the peelable sheets, to open such a container, an outlet,positioned to be in communication with an opened container, throughwhich a user can inhale medicament in powder form from such an openedcontainer, and indexing means for indexing in communication with theoutlet containers of a medicament pack in use with the inhalationdevice.

Referring now to FIGS. 2 and 3, these show an inhalation device in whichis mounted a flexible strip 101 defining a plurality of pockets 102 eachof which contains a dose of medicament which can be inhaled, in the formof a powder. The strip 101 comprises a base sheet 103 in which blistersare formed to define the pockets 102, and a lid sheet 104 which ishermetically sealed to the base sheet 103 except in the region of theblisters, in such a manner that the lid sheet and the base sheet can bepeeled apart. The sheets are sealed to one another over their wholewidth except for leading end portions thereof where they are preferablynot sealed to one another at all. The lid and base sheets are eachpreferably formed of a plastics/aluminium laminate, and the lid and basesheets are preferably adhered to one another by heat sealing. By way ofexample, the lid material may be a laminate consisting of 50 gsm bleachkraftpaper/12 micron polyester (PETP) film/20 micron soft temperaluminium foil/9 gsm vinylic peelable heat seal lacquer (sealable toPVC), and the base material may be a laminate consisting of 100 micronPVC/45 micron soft temper aluminium foil/25 micron orientated polyamide.The lacquer of the lid material is sealed to the PVC layer of the basematerial to provide the peelable seal between the lid and base sheets.

The strip 101 is shown as having elongate pockets which run transverselywith respect to the length of the strip. This is convenient in that itenables a large number of pockets to be provided in a given striplength. The strip may, for example, be provided with sixty or onehundred pockets, but it will be understood that the strip may have anysuitable number of pockets.

The inhalation device comprises a body 110 defining three storagechambers, namely a chamber 111 in which the strip 101 is initiallyhoused and from which it is dispensed, a chamber 112 for receiving theused portion of the base sheet 103, and a chamber 113 within which theused portion of the lid sheet can be wound up on a wheel 114. Thechambers 111 and 112 contain respective curved leaf springs 128 and 129,the purpose of which is described below. The body defines a furtherchamber 115 which houses an index wheel 116. This has a plurality ofgrooves 117 extending parallel to the axis of the wheel 116. The groovesare spaced at a pitch which is equal to the distance between the centrelines of adjacent pocket 102. The chambers 111, 112, 113 and 115 areclosed by a lid 130. The chamber 115 communicates with the chambers 111,112 and 113 via passages 131, 133 and 132 respectively.

The chamber 115 communicates via a slit 118 which, in turn, extendsupwardly within a mouthpiece 120. The slot 118 also communicates withair inlets, as will be described below with reference to the specificmouthpiece shown in FIGS. 4 a and 4 b. The mouthpiece 120 is providedwith additional air inlets 121 shown here in the form of a pair ofcircular apertures, though they may be of some other shape, as they arein FIGS. 4 a and 4 b. The primary purpose of the additional air inlets121 is to provide additional air to the user and thus reduce theresistance to inhalation, though they may serve one or more additionalpurposes, as they do in FIGS. 4 a and 4 b and as is described below withreference to those Figures.

A means is provided by which the user can rotate the index wheel and thelid wheel in steps of a predetermined size. This means comprises aratchet wheel 122 and a gear wheel 123, both connected to rotate inunison with the index wheel 116, a lever 124 arranged to rotate aboutthe same axis as the ratchet wheel 122 and gear wheel 123, butindependently thereof, and a gear wheel 125 which meshes with the gearwheel 123 and is arranged to rotate the lid wheel 114. The lever 124carries a pusher arm 126, the end of which is arranged to engage theteeth of the ratchet wheel 122. The teeth of the ratchet wheel are alsoengaged by a pawl 127 fixedly secured to the body 110. For reasons whichwill become apparent from the description below of the operation of thisembodiment, the gear wheel 125 is not connected directly to the lidwheel 114, but is connected via a slipping clutch 150 which is housedwithin the lid wheel 114. The effect of the provision of this clutch isthat slipping occurs between the lid wheel and the gear wheel 125 whenthe force required to rotate the lid wheel exceeds a predeterminedamount.

The clutch 150 comprises a disc 151 provided with radially extendingserrations 152, or other surface roughness, which is held in engagementwith a similarly serrated or roughened surface 153 provided on an endface of the lid wheel 114 by a compression spring 154. The spring 154bears at one end against an inwardly directed surface 155 of the lidwheel and at the other end against a nut 156 threaded on a bolt 157.

The device described above can be made so as to be reusable after thedoses of medicament contained in the pocket 102 have all been dispensed.In that case, provision can be made for the user to gain access to theinterior of the device, for example by removing the lid 130, so as toinsert therein a fresh strip 101, for example in a cassette.Alternatively, however, the device may be made to be disposable once thestrip 101 with which it is supplied has been used up.

In either event, when the device is first used the bulk of the strip 101is within the chamber 111, kept in a relatively tight reel by the leafspring 128, with a short portion at the leading end thereof passing outof the chamber 111 through the passage 131 to the index wheel 116. Theforemost part of the leading end of the strip is peeled apart so thatthe leading end of the lid sheet 104 can be secured to the lid wheel114, and so that the leading end of the base sheet 103 can enter thepassage 133. The end of the lid sheet 104 is held in place on the lidwheel 114 by means of a key 134 which is a force fit in a slot 135 inthe wheel 114.

A user desiring to use the device pushes the lever 124 in ananticlockwise direction, as viewed in FIG. 2, so that the pusher arm 126urges the ratchet wheel 122 through an angle equal to the angulardistance between two adjacent teeth. This causes the ratchet wheel 116to rotate by an angular amount equal to the pitch of the groove 117thereof and thus equal to the distance between two adjacent pocket 102in the strip 101. This brings a pocket 102 opposite the slot 118 in thebody 110. Since the ratchet wheel 122 and gear wheel 123 move in unison,and since the gear wheel 125 meshes with the gear wheel 123, movement ofthe lever 124 also causes the lid wheel 114 to rotate. This peels asufficient portion of the lid sheet 104 away from the base sheet 103 toexpose the contents of the pocket 102 which is being brought intoalignment with the slot 118.

When the user inhales through the mouthpiece 120 the flow of air whichthis produces entrains powder from the opened pocket, so that the powderis inhaled by the user. One way in which this can occur is explained inmore detail below with reference to the embodiment of mouthpiece shownin FIGS. 4 a and 4 b. Each time the above procedure is repeated afurther length of lid sheet is wrapped around the lid wheel 114 and afurther length of base sheet enters chamber 112 through passage 133. Theleaf spring 129 therein ensures that the base sheet is coiled up anddoes not snag on the wall of the chamber 112.

One effect of winding up the lid sheet on the lid wheel 114 is that theexternal diameter of the wheel plus the sheet wound thereon graduallyincreases. Were it not for the use of a slipping clutch to connect thegear wheel 125 to the lid wheel 114 this would have the result thatsuccessive operations of the lever 124 would try to cause aprogressively longer length of lid sheet to be wound on to the lidwheel. The slipping clutch 150, however, avoids this effect, the clutchslipping each time by an amount sufficient to ensure that for everyoperation of the lever the amount of lid sheet wound on is preciselyequal to the pitch of the pocket 102.

FIGS. 4 a and 4 b show a portion of the index wheel 116 with a pocket102 therein, in conjunction with a mouthpiece which differs slightlyfrom the mouthpiece 120 shown in FIGS. 2 and 3, and which is denoted byreference numeral 120. The mouthpiece 120 has air inlets 140, to whichreference in general terms has already been made in connection withFIGS. 2 and 3, and a central powder outlet 119, one end of which is opento the pocket 102 and the other end of which opens into the interior ofthe mouthpiece 120.

When a user inhales through the mouthpiece 120 this causes air to flowin through the inlets 140 and thence through the pocket 102, into thepowder outlet 119, and out through the mouthpiece 120. By thus directingthe flow of air through the pocket 102, efficient entrainment of powderin the airflow is achieved, with consequent efficient emptying of thepocket. The mouthpiece 120 is provided with additional air inlets 121,shown here by way of example as being four in number, which opentangentially into the mouthpiece. When the user inhales air is drawninto the mouthpiece not only through the air inlets 140 but also throughthe air inlets 121, and the air entering through the inlets 121 producesa swirling airflow which helps to distribute powder effectively withinthe airflow and reduce the extent to which powder is deposited on theinside of the mouthpiece. This also helps to break up any aggregates ofpowder which may be present in the blister.

A third embodiment of the inhalation device according to the inventionis shown in FIGS. 5 and 6. This is intended for use with a strip 201,similar to the strip 101 used in the second embodiment shown in FIGS.2-3, except as regards the spacing of the pockets (for which see below).In many respects the third embodiment resembles the second embodiment,and components in the third embodiment which correspond in general termsto particular components in the second embodiment are denoted by thesame reference numerals, but with the addition of 100. The maindifference between the second embodiment and the third embodiment isthat in the latter there is no index wheel corresponding to the indexwheel 116 of the second embodiment. Instead, indexing of the strip 201,to ensure that each operation of the lever advances the strip by anamount equal to the pitch of the pockets, is achieved by a resilientlyflexible arm 250 terminating in a tooth 252 which engages betweenadjacent pockets. Each time the lever 224 is operated the arm 250 isresiliently depressed as a pocket slides past the tooth 252 thereof, andthe tooth then springs back into engagement with the strip to the rearof the pocket which has just passed it.

It will be appreciated that, as in the case of the second embodiment,the diameter of the lid wheel 214 with the lid sheet thereon graduallyincreases during operation. Since a slipping clutch cannot be used inthis embodiment the effect just described is compensated by having thespacing of the pocket 202 gradually increasing towards the rear end ofthe strip.

One other difference which will be noted between the second and thirdembodiments, is that in the latter the chambers 211 and 212 form asingle composite chamber, unlike the separate chambers 111 and 112 inthe second embodiment. However, this need not be so, and the secondembodiment could use a single composite chamber and the third embodimentcould use separate chambers.

FIG. 7 shows a fourth embodiment. In many respects this resembles thethird embodiment, and components in the fourth embodiment whichcorrespond in general terms to components in the third embodiment aredenoted by the same reference numerals but with the addition of afurther 100.

One difference which will be observed between the third and fourthembodiments is that in place of the lid wheel 114 a pair of wheels 314 aand 314 b are employed, with the lid sheet being gripped in the nipbetween the wheels 314 a and 314 b, which act as a mangle. These wheelsare knurled or otherwise roughened to improve the grip between thewheels and the lid sheet. The used lid sheet is not wound up but is fedinto a chamber 313, so that no problem arises, as it does in the secondand third embodiments, with the lid wheel attempting to wind upprogressively longer lengths of lid as operation of the devicecontinues.

FIG. 8 shows the mouthpiece to be of a somewhat different design to thatshown in FIGS. 4 a and 4 b. The mouthpiece is shown as having a singleair inlet 340 in place of the pair of air inlets 140, and the powderoutlet 119 of FIGS. 4 a and 4 b is replaced by a mouthpiece portion 319of reduced width. It should be understood, however, that the deviceshown in FIG. 7 could be modified so as to incorporate a mouthpiece moreclosely resembling FIGS. 4 a and 4 b.

FIGS. 9 to 12 show a fifth embodiment of the invention. This is similarin the principle of its operation to the second embodiment, andcomponents in the fifth embodiment which correspond in general terms tocomponents in the second embodiment are denoted by the same referencenumerals but with the addition of 300.

As in the second embodiment, the device receives a flexible strip, heredenoted as 401, comprising a base sheet 403 in which pocket 402 aredefined and a lid sheet 404. The strip 401, is shown most clearly inFIG. 13. The lid sheet 404 has a loop 404 a formed at the leading endthereof for engagement over a post 471 a extending upwardly from atoothed wheel 471 (described below). The base sheet has a lead portion403 a of reduced width for engagement in a slot 470 a formed in the basewinding wheel 470 (described below). The leading end portions of thebase sheet and lid sheet are not sealed together, as can be seen in FIG.13.

The body 410 comprises a base 410 a and a top 410 b both of generallycircular shape. When the device is assembled the base and top aresnap-fitted together. The body defines a single internal chamber withinwhich the strip 401 is housed and within which are also housed a wheel414 for winding up the used portion of the lid sheet 404, a base windingwheel 470 and an index wheel 416. The index wheel 416 is hollow and anindex ratchet wheel 422 is housed within it. All the wheels justmentioned are mounted in the chamber defined by the body, for rotationalmovement with respect thereto. A pawl 470 b is attached to the body 410and engages the teeth of the base winding wheel 470 to prevent the wheelmoving anticlockwise, thus ensuring that the strip 401 can only proceedforwards through the device.

The lid winding wheel 414 is formed in two parts, namely a toothed wheel471 having teeth 472 and a shaft 473, and a collapsible wheel 474 havinga hollow central shaft 475 and a plurality of resilient arms 476, forexample, as shown, eight such arms, extending from the central shaft 475each at an angle to a radius. The toothed wheel 471 has a lug 477 whichengages in a corresponding notch in the shaft 475 so that the wheels 471and 474 rotate in unison.

The hollow index wheel 416 has external teeth 478 which mesh with theteeth of the base winding wheel 470 and the teeth of the wheel 471.Ratchet teeth 479 are formed on the internal walls of the index wheel416, and the index ratchet wheel 422 has two pawls 480 which engage theratchet teeth 479.

The device further comprises a lever 424 which comprises an arcuate wall481 with a finger tab 482, and an arm 483 which extends inwardly fromthe wall 481 and carries an arcuate array of teeth 484 at its distalend. The lever is pivotally mounted to the centre of the base 410 a formovement about an axis which is at the centre of the pitch circle of theteeth 484, the teeth 484 mesh with the teeth 485 on the index ratchetwheel 422.

A manifold 486 provides communication between the chamber within thebody 410 and a mouthpiece 420. The manifold has a powder outlet 419 andalso has a passageway 487 to allow used lid strip 404 to pass to thecollapsible wheel 474. Optionally, a roller 488 may be provided to guidethe strip 404 into the passageway 487.

A dose monitor ring 489 having teeth 490 is arranged to be rotatablewithin the body base 410 a. On its lower surface this bears indicia (notvisible in the drawings) which can be viewed by the user through awindow 494 in the body 410. It will be noted from FIGS. 12 a to 12 dthat the window can be seen both when the cover 491 (see below) isclosed and when it is open. The indicia indicate either exactly orapproximately the number of doses left (or the number of doses used, ifpreferred). The ring 489 is rotated by virtue of the fact that its teeth490 are engaged by the teeth 478 of the index wheel.

The device is provided under a cover 491 which is pivotally mounted onthe body 410 by means of a lug 492 on the body top 410 b and acorresponding lug 493 on the body base 410 a. The cover is pivotalbetween an open position (shown in FIG. 10) in which the mouthpiece isexposed and a closed position in which it is not, as is described morefully below.

In operation, the user moves the cover 491 to its open position and thenpresses on the finger tab 482 of the lever 424 to cause it to move asthe lever pivots. This makes the index ratchet wheel 422 rotate which,via the pawls 480, causes the index wheel 416 also to rotate. Rotationof the index wheel 416 produces rotation of both the base winding wheel470 and the lid winding wheel 414, thus peeling the base sheet and lidsheet apart over a distance sufficient to expose a previously unopenedpocket 402 opposite the end of the powder outlet 419 in the manifold486. The patient can then inhale through the mouthpiece, as in thepreceding embodiments.

Successive stages in the operation of the device are shown in FIGS. 12 ato 12 d. The device is in its closed position in FIG. 12 a. The fingertab 482 of the lever 424 is at this stage in a recess 482 b formed inthe body 410 (seen more clearly in FIGS. 12 b and 12 c). The cover 419is held stationary as the body 410 is rotated anticlockwise, a recess410 c being provided in the periphery of the body to enable the user toinsert a finger for this purpose. The device is thus moved to the partlyopen position shown in FIG. 12 b. During this process the lever 424remains stationary with respect to the cover 491. This is achieved bythe lever being provided internally with a resilient arm 424 a the tip424 b of which engages in a recess 491 a in the cover 491. The arm 424 ais attached to the lever 424 via a cylindrical member 424 c. As viewedin FIG. 12 a, the arm 424 a extends anticlockwise from the member 424 cover an arc of about 90°. The cylindrical member 424 c is guided in anarcuate slot 410 d formed in the body 410. The slot 410 d extendsthrough an arc of about 180°, and in FIG. 12 a the member 424 c is shownas being approximately half way along its length. In FIG. 12 b it isshown as being at one end.

The user continues to rotate the body 410 from the position shown inFIG. 12 b to the position shown in FIG. 12 c. During this furtherrotation tip 424 b of the arm 424 a jumps out of the recess 491 a. Thisoccurs because, with the member 424 c at one end of the slot 410 d,movement of the body 410 carries the member 424 c with it in ananticlockwise direction and hence compels the arm 424 a likewise to moveanticlockwise. The user then moves the lever 424 by pushing on thefinger tab 482 to cause it to rotate anticlockwise through the positionshown in FIG. 12 c to the position shown in FIG. 12 d where the fingertab 482 re-enters the recess 482 b. The steps thus far described bothexpose the mouthpiece 420 and open a fresh blister. The device istherefore now ready for the user to inhale.

After use, the body 410 is rotated clockwise, the lever 424 moving inunison with the body, to bring the device back to the position of FIG.12 a.

It will be noted that the collapsible wheel 474 in effect assumes thefunction of the clutch in the first embodiment. As more lid sheet iswound onto the wheel 474 the arms 476 gradually flex inwardly, and theeffect is to keep the external diameter of the reel of wound up lidsheet substantially constant, while the internal diameter thereofgradually decreases.

Although in the embodiment of FIGS. 9 to 12, the base sheet is wound upas well as the lid sheet, it is not necessary for there also to be aslipping clutch or the like between the index wheel and the base windingwheel. The diameter of the base winding wheel is so chosen thatinitially the base sheet is wound up only very loosely, and thetightness with which the sheet is wound increases during operation butwithout ever reaching an unacceptable level. In theory, the base sheetcould be wound up precisely via a slipping clutch or the like, with thelid sheet being only loosely wound, but in practice it is much easier towind up the lid precisely because it is flat and because it is thinnerthan the base sheet.

In another preferred embodiment according to the invention, the inhaleraccording to U.S. Pat. No. 4,627,432 is applied. The disclosure of U.S.Pat. No. 4,627,432 is incorporated herein by reference in its entirety.

U.S. Pat. No.4,627,432 relates to devices by which a medicament can beadministered to or by patients inhaling through the devices. Themedicaments may be in solid finely divided form or fluid form. Suchdevices are now quite well known for administering medicaments containedin capsules to patients suffering from bronchial conditions such as, forexample, bronchial asthma.

It is well known for medicament in powder or other finely divided formto be supplied in capsules which are loaded by a patient into such adevice which is sometimes called an “insufflator”. The medicament isthen released from the capsule and inhaled by the patient, usuallythrough the mouth, but sometimes through the nose.

There are disadvantages in the use of capsules, which are made ofgelatin, to contain medicaments. Gelatin is relatively unstable and islacking in physical strength so that the capsules need to be protectedby packaging, for example in glass bottles. Environmental degradation ofboth the capsules and their contents may occur in a relatively shorttime.

An object of the present invention is to provide a more convenient wayof administering medicament to such patients than has been possiblehitherto and which avoids the need to pack medicaments in capsules. Thedevice of the present invention makes use of the technique of packingmedicaments by loading them in blister packs, that is to say, packscomprising a sheet, which may be laminated, of foil or plastics materialwhich acts as a carrier and which is provided with a number of breakableor openable containers called “blisters” incorporating a sheet securedon a first sheet to form a cover or lid. Such blister packs are incommon use with tablets of one kind or another, but we have discoveredthat they can also be used with medicaments in finely divided solidform.

The device of the invention is suitable for administering a variety ofmedicaments such as, for example, salbutamol, beclomethasonedipropionate and disodium cromoglycate.

Accordingly, in a preferred embodiment, the invention relates to amethod for the administration of an inhalable powder containingtiotropium, preferably in an amount of 0.001% to 5%, in admixture with aphysiologically acceptable excipient with an average particle size ofbetween 10 μm to 500 μm, by means of the inhaler according to U.S. Pat.No. 4,627,432, being characterized by a housing with a chamber therein,an air inlet into the chamber, a circular disc having an axissubstantially coaxial to the chamber axis and rotatable inside thechamber and provided with a plurality of apertures therethrough arrangedin a circle, the apertures being sized and positioned so that eachaperture is adapted to be aligned with a different container, the discbeing arranged so that the carrier can be placed in contact with oneface of the disc with one of the containers located in each one of theapertures, an outlet through which a patient may inhale leading out ofthe chamber, an opening in the housing alignable with respective ones ofthe apertures in the disc as the disc is rotated, a plunger operativelyconnected to the housing and having a penetrating member, thepenetrating member being displaceable to pass through the opening andthe corresponding aperture in the disc registered with it thereby topenetrate and open a container located in the aperture so that themedicament will be released from the container and entrained in the airflow produced by a patient inhaling through the outlet, and meansbetween the disc and the housing for rotatably indexing the disc toregister each of the apertures in turn with the housing opening.

In another embodiment, the invention relates to a method for treatmentof airway diseases, particularly chronic obstructive pulmonary diseaseand asthma, characterized in that an inhalable powder containingtiotropium, preferably in an amount of 0.001% to 5%, in admixture with aphysiologically acceptable excipient with an average particle size ofbetween 10 μm to 500 μm, is administered via inhalation by the inhaleraccording to U.S. Pat. No. 4,627,432, being characterized by a housingwith a chamber therein, an air inlet into the chamber, a circular dischaving an axis substantially coaxial to the chamber axis and rotatableinside the chamber and provided with a plurality of aperturestherethrough arranged in a circle, the apertures being sized andpositioned so that each aperture is adapted to be aligned with adifferent container, the disc being arranged so that the carrier can beplaced in contact with one face of the disc with one of the containerslocated in each one of the apertures, an outlet through which a patientmay inhale leading out of the chamber, an opening in the housingalignable with respective ones of the apertures in the disc as the discis rotated, a plunger operatively connected to the housing and having apenetrating member, the penetrating member being displaceable to passthrough the opening and the corresponding aperture in the discregistered with it thereby to penetrate and open a container located inthe aperture so that the medicament will be released from the containerand entrained in the air flow produced by a patient inhaling through theoutlet, and means between the disc and the housing for rotatablyindexing the disc to register each of the apertures in turn with thehousing opening.

In another preferred embodiment, the invention relates to the use of theinhaler according to U.S. Pat. No. 4,627,432 being characterized by ahousing with a chamber therein, an air inlet into the chamber, acircular disc having an axis substantially coaxial to the chamber axisand rotatable inside the chamber and provided with a plurality ofapertures therethrough arranged in a circle, the apertures being sizedand positioned so that each aperture is adapted to be aligned with adifferent container, the disc being arranged so that the carrier can beplaced in contact with one face of the disc with one of the containerslocated in each one of the apertures, an outlet through which a patientmay inhale leading out of the chamber, an opening in the housingalignable with respective ones of the apertures in the disc as the discis rotated, a plunger operatively connected to the housing and having apenetrating member, the penetrating member being displaceable to passthrough the opening and the corresponding aperture in the discregistered with it thereby to penetrate and open a container located inthe aperture so that the medicament will be released from the containerand entrained in the air flow produced by a patient inhaling through theoutlet, and means between the disc and the housing for rotatablyindexing the disc to register each of the apertures in turn with thehousing opening, for the administration of an inhalable powderedcontaining tiotropium, preferably in an amount of 0.001% to 5%, inadmixture with a physiologically acceptable excipient with an averageparticle size of between 10 μm to 500 μm.

In yet another preferred embodiment, the invention relates to aninhalation kit consisting of an inhalable powdered containingtiotropium, preferably in an amount of 0.001 to 5%, in admixture with aphysiologically acceptable excipient with an average particle size ofbetween 10 to 500 μm, and the inhaler according to U.S. Pat. No.4,627,432, being characterized by a housing with a chamber therein, anair inlet into the chamber, a circular disc having an axis substantiallycoaxial to the chamber axis and rotatable inside the chamber andprovided with a plurality of apertures therethrough arranged in acircle, the apertures being sized and positioned so that each apertureis adapted to be aligned with a different container, the disc beingarranged so that the carrier can be placed in contact with one face ofthe disc with one of the containers located in each one of theapertures, an outlet through which a patient may inhale leading out ofthe chamber, an opening in the housing alignable with respective ones ofthe apertures in the disc as the disc is rotated, a plunger operativelyconnected to the housing and having a penetrating member, thepenetrating member being displaceable to pass through the opening andthe corresponding aperture in the disc registered with it thereby topenetrate and open a container located in the aperture so that themedicament will be released from the container and entrained in the airflow produced by a patient inhaling through the outlet, and meansbetween the disc and the housing for rotatably indexing the disc toregister each of the apertures in turn with the housing opening.

In the embodiment of the invention illustrated in FIGS. 14 and 15 of thedrawings, a medical administration device comprises a shallowcylindrical housing 501 of a plastics material which has a cylindricalchamber 502 therein. The chamber is closed at one end 503, hereinconsidered the bottom of the chamber, and a removable cover 504 is aclose fit over the chamber at the other end.

A mouthpiece outlet 505 projects outwardly from the cylindrical wall ofthe housing 501 and communicates with the interior of the chamber 502. Aperforated guard not shown, is provided in the mouthpiece to prevent anysolid particles of an undesirably large size being inhaled by a patientinhaling through the mouthpiece.

A rim or shoulder 506 runs round the inside wall of the chamber 502 toprovide an annular support on which a blister pack 507 may be located.

The blister pack 507 can conveniently be a foil laminate with aplurality of frangible containers or “blisters” 508 arranged in acircle. The blisters 508 are filled with medicament in particulate form,having a particle size in the range of 0.5-10 microns. The medicamentmay be with a pharmaceutically acceptable carrier such as lactose orstarch in particulate form. Alternatively, the medicament may be inliquid form. The blister pack is of circular disc form, and is removablyfitted inside the chamber so that it is replaceable when the individualdoses of medicament contained in the blisters have been discharged.

The chamber 502 contains a central open cylindrical support column 509upstanding from the bottom wall 503 of the chamber. A clamp disc member510 is removably fitted inside the chamber 502 and has on its undersidea plurality of locating pegs, not shown, which pass through the blisterpack by an appropriate method and engage inside the support column. Theclamp member 510 is rotatable inside the chamber. In use, the clampmember is placed on top of a blister pack 507 which has already beenloaded into the chamber and is located on the support shoulder 506. Theblister pack 507 is preferably a circular disc of foil laminate materialwith blisters or containers 508. The clamp member 510 has a plurality ofapertures 511 which are arranged in a circle and so spaced from eachother that each of them will receive one of the blisters 508 of theblister pack 507. A knob 512 is upstanding from the clamp member 510 andwhen the lid 504 is fitted on the housing 501 the knob 512 will projectthrough an aperture 513 in the top of the lid 504. This knob can beturned by the patient to rotate the clamp member 510 and since theblisters 508 of the blister pack 507 are located in the apertures 511 inthe clamp plate 510 rotation of the clamp member will also rotate theblister pack. A plurality of protuberances or pips 514 are provided onthe top of the clamp member 510 and engage in a recess 515, FIG. 15, onthe underside of the cover 504 to make sure that the clamp plate iscorrectly aligned in position. As will be seen, the knob 512 is flutedto provide openings between the knob and the hole 513 through which aircan enter the chamber 502 from the outside.

The cover 504 also has an aperture 516 in which a plunger 517 containedin a plunger housing 518 can be received. The plunger has an annularshoulder 519 and a spring 520 can bear between the shoulder 519 and thebottom of the plunger housing 518 to urge the plunger into an upper orinoperative position. The plunger may be provided with a knife edge 521or other means to enable the blister to be opened. When the plunger 517is depressed against the action of the spring 520, the lower edgeportion 521 of the plunger will pass through an aperture 522 in theplunger housing to pass through a blister 508 located in register withthe plunger. Such engagement will open the blister, and permit therelease of medicament therefrom. This action will so open the blisterthat when a patient inhales air will pass through the blister, themedicament being entrained in the air flow and exiting through themouthpiece 505 via a transfer cavity 523 inside the chamber incommunication with the mouthpiece 505. By rotation of the knob 512 theclamp member 510 and the blister pack 507 can be rotated to bring eachblister in turn into location beneath the plunger. The variousprotuberances or pips 14 will in turn engage in the recess 515 to makesure that the blister pack is correctly registered with the plunger.

It is not essential that the plunger have a knife 521 to open theblister. If desired a needle can be used to perforate the blister or theplunger may have a pointed end or even a blunt end or any otherconvenient opening means may be used.

In use, the patient needing a dose of medicament may hold the devicewith the mouthpiece in his mouth. The patient then depresses the plungerto open the blister and give access to the medicament therefrom andinhales through the mouthpiece so that the medicament will be entrainedin the air flow and will enter the lungs of the patient. If desired, themouthpiece can be provided with air inlet apertures 525 to improve theair flow as the patient inhales.

In a modification not illustrated the underside of the blister pack canbe supported on another clamp plate instead of the support rim orshoulder 506.

The blister pack is conveniently arranged to provide a sufficient numberof individual doses for a patient for use during a convenient periodsuch as one day or more. The housing can be modified by providing anadditional chamber, not visible, at the bottom, this additional chamberbeing closed by a removable cover 526. This additional chamber can beused to store replacement blister packs.

The mouthpiece may, if desired, be arranged so that a patient may use itto inhale through the nose.

A modified device which does not use the clamp member 510 is illustratedin FIGS. 16 and 17. The device of this modification comprises a housing530 having a chamber 531 therein. A mouthpiece 532 projects outwardlyfrom the cylindrical wall of the housing 530 in a generally radialdirection and communicates with the interior of the chamber 531. Aperforated guard 533 is provided at the entrance to the mouthpiece 532.A rim or shoulder 34 runs round the inside wall of the chamber 31 toprovide an annular support for a support member 535 in the form of acircular plate or disc. This support member is arranged to receive ablister pack 536. The blister pack 536 has a plurality of frangiblecontainers 537 arranged in a circular row. These containers are in theform of “blisters” of a generally conical form as clearly shown in FIG.17 and contain a medicament as described with reference to FIG. 14. Thesupport member 535 has a plurality of holes 538 equal in number to thenumber of blisters 537 of the blister pack 536. The conical portion ofone blister 537 is located in each of the holes 538 when the device isloaded and in use. An external rotatable member 539 with a knurled edge540 is located in face contact with the bottom of the housing 530. Aspindle or the like 541 with radial projections 542 extends centrallyfrom the support member 535 through a hole 543 in the bottom of thehousing 530 and into an opening 544 of complementary shape in a spigot545 of the member 539. The spigot 545 passes through the hole 543 andthe spindle 541 and 542 engages in the opening 544 so that rotation ofthe member 539 will cause similar rotation to the support member 535. Aremovable cover 546 fits on top of the housing 530. An opening 547 isprovided in the cover 546 and engages a projection 548 in the housing530 so as correctly to locate the cover. The cover 546 carries a bracket549 on which a lever or trigger 550 is pivotally mounted. A plunger 551is located on the lever or trigger 550 and extends through a hole 552 inthe cover. A spring 553 is provided to bear between the trigger or lever550 and the top of the cover 546 to urge the lever or trigger upwards.

The hole 552 is so positioned that each hole 538 in the support member535 will register with this hole as the support member 535 is rotated.

When one of the holes 538 is in register with the hole 552 the trigger550 can be depressed so that its plunger 551, which may be in the formof a needle, will pierce through the blister 537 located in that hole(i.e. pierce the top and the bottom of the blister) thereby to permitpowder to exit from the blister. Some powder will fall into a tray-likecompartment 554 inside the chamber 531. When the patient inhales, airpasses through the pierced blister so that powder will be entrained inthe airflow and will, with powder from the compartment 554, be withdrawnthrough the guard 533 and the mouthpiece 532. When the device is not inuse, the mouthpiece 532 can be enclosed in a mouthpiece cover or sheath555 which has a channel-like extension 556 which will engage with thebracket 549 to prevent the plunger 551 being depressed to enter throughthe hole 537.

When the device is in use and the patient inhales through the mouthpiece532 it is, of course, essential for air to be able to enter the interiorof the chamber 531. Any suitable air inlets can be provided.Conveniently, however, air can enter through the hole 552 the plunger orneedle 551 being smaller in diameter than the diameter of the hole 552so that it serves as an air inlet.

The following Examples serve to illustrate the present invention furtherwithout restricting its scope to the embodiments provided hereinafter byway of example.

Starting Materials

As a starting material for the synthesis of crystalline tiotropiumbromide monohydrate tiotropium bromide obtained according to thedisclosure of European patent application EP 418 716 A1 is be used.

Preparation of Crystalline Tiotropium Bromide Monohydrate

15.0 kg of tiotropium bromide as obtained according to the methodsdisclosed in EP 418 716 A1 are added to 25.7 kg of water in a suitablereaction vessel. The mixture is heated to 80° C. to 90° C. and stirredat constant temperature until a clear solution is formed. Activatedcharcoal (0.8 kg) moistened with water, is suspended in 4.4 kg of water,this mixture is added to the solution containing the tiotropium bromideand rinsed with 4.3 kg of water. The mixture thus obtained is stirredfor at least 15 minutes at 80° C. to 90° C. and then filtered through aheated filter into an apparatus which has been preheated to an outertemperature of 70° C. The filter is rinsed with 8.6 kg of water. Thecontents of the apparatus is cooled at 3° C. to 5° C. every 20 minutesto a temperature of 20° C. to 25° C. The apparatus is further cooled to10° C. to 15° C. using cold water and crystallization is completed bystirring for at least one hour. The crystals are isolated using asuction drier, the crystal slurry isolated is washed with 9 liters ofcold water (10° C. to 15° C.) and cold acetone (10° C. to 15° C.). Thecrystals obtained are dried in a nitrogen current at 25° C. over 2hours. Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory)

The crystalline tiotropium bromide monohydrate thus obtained ismicronized by known methods, to bring the active substance into theaverage particle size which meets the specifications according to theinvention.

The DSC diagram of crystalline tiotropium bromide monohydrate shows twocharacteristic signals. The first, relatively broad, endothermic signalbetween 50° C. to 120° C. can be attributed to the dehydration of thetiotropium bromide monohydrate to produce the anhydrous form. Thesecond, relatively sharp endothermic peak at 230° C.±5° C. can be putdown to the melting of the substance. These data were obtained using aMettler DSC 821 and evaluated with the Mettler STAR software package.These data, like the other values given in the above Table, wereobtained at a heating rate of 10 K/min.

The crystalline tiotropium bromide monohydrate thus obtained wascharacterized by IR spectroscopy. The data was obtained using a NicoletFTIR spectrometer and evaluated with the Nicolet OMNIC software package,version 3.1. The measurement was carried out with 2.5 μmol of tiotropiumbromide monohydrate in 300 mg of KBr. Table 1 shows some of theessential bands of the IR spectrum.

TABLE 1 Attribution of Specific Bands Wave Number (cm⁻¹) AttributionType of Oscillation 3570, 410 O—H elongated oscillation 3105 Aryl C—Helongated oscillation 1730 C═O elongated oscillation 1260 Epoxide C—Oelongated oscillation 1035 Ester C—OC elongated oscillation  720Thiophene cyclic oscillation

The crystalline tiotropium bromide monohydrate was characterized byX-ray structural analysis. The measurements of X-ray diffractionintensity were carried out on an AFC7R-4-circuit diffractometer (Rigaku)using monochromatic copper K_(α) radiation. The structural solution andrefinement of the crystal structure were obtained by direct methods(SHELXS86 Program) and FMLQ-refinement (TeXsan Program). The X-raystructural analysis carried out showed that crystalline tiotropiumbromide hydrate has a simple monoclinic cell with the followingdimensions: a=18.0774 Å, b=11.9711 Å, c=9.9321 Å, β=102.6910°, V=2096.96Å³.

The following machines and equipment, for example, may be used toprepare the inhalable powders according to the invention:

Mixing Container or Powder Mixer: Gyrowheel mixer 200 L; type: DFW80N-4;made by: Messrs Engelsmann, D-67059 Ludwigshafen.

Granulating Sieve: Quadro Comil; type: 197-S; made by: Messrs Joisten &Kettenbaum, D-51429 Bergisch-Gladbach.

The following examples provide for inhalable powder mixtures applicableaccording to the invention.

EXAMPLE 1

5.2 kg of glucose monohydrate for inhalation (average particle size 25μm) is used as the excipient. 22.5 g crystalline tiotropium bromidemonohydrate (micronized; average particle size 1 μm to 3.5 μm) is usedas the active ingredient.

The aforementioned components are sieved in in alternate layers oflactose monohydrate in batches of about 200 g and crystalline tiotropiumbromide monohydrate in batches of about 1 g. The ingredients sieved inare then mixed together (mixing at 900 rpm).

According to the invention, preferably 5.2225 mg of the aforementionedpowder is delivered per dose.

EXAMPLE 2

5.4775 kg of lactose monohydrate for inhalation (average particle size25 μm) is used as the excipient. 22.5 g crystalline tiotropium bromidemonohydrate (micronized; average particle size 1 to 3.5 μm) is used asthe active ingredient.

The aforementioned components are sieved in in alternate layers oflactose monohydrate in batches of about 200 g and crystalline tiotropiumbromide monohydrate in batches of about 1 g. The ingredients sieved inare then mixed together (mixing at 900 rpm).

According to the invention, preferably 5.5 mg of the aforementionedpowder are delivered per dose.

EXAMPLE 3

1.1: Excipient Mixture

5.203 kg of lactose monohydrate for inhalation (average particle size 25μm) is used as the coarser excipient component. 0.27 kg of lactosemonohydrate (5 μm) is used as the finer excipient component. In theresulting 5,473 kg of excipient mixture, the proportion of the finerexcipient component is 5%.

The aforementioned components are sieved in in alternate layers oflactose monohydrate (25 μm) in batches of about 200 g and lactosemonohydrate (5 μm) in batches of about 10 g. The ingredients sieved inare then mixed together (mixing at 900 rpm).

1.2: Final Mixture

To prepare the final mixture, 5,473 kg of the excipient mixture (1.1)and 22.5 g crystalline tiotropium bromide monohydrate (micronized;average particle size 1 μm to 3.5 μm) are used. The content of activesubstance in the resulting powder is 0.4%.

The aforementioned components are sieved in in alternate layers ofexcipient mixture (1.1) in batches of about 200 g and crystallinetiotropium bromide monohydrate in batches of about 1 g. The ingredientssieved in are then mixed together (mixing at 900 rpm).

According to the invention preferably about 5.5 mg of the aforementionedpowder are delivered per dose.

1-21. (canceled)
 22. A medical product comprising a single dry powderdose of micronized tiotropium powder which is the free ammonium cationof tiotropium or the free ammonium cation of tiotropium and acounter-ion which is selected from the group consisting of chloride,bromide, iodide, methanesulfonate, p-toluenesulfonate or methylsulfate,said single dry powder dose being directly loaded into a containeradapted for administration by a dry powder inhaler, wherein thecontainer is hermetically sealed, thereby preserving at least seven ofthe single dry powder doses of the micronized tiotropium powder doseagainst environmental degradation, wherein said hermetically sealedcontainer prevents ingress of moisture into said container, wherein atleast seven of the single dry powder doses of the micronized tiotropiumpowder dose are preserved against environmental degradation for a periodof at least seven days, wherein said hermetically sealed containercomprises at least one of a formed aluminum foil and a flat aluminumfoil, optionally laminated with a plastic; or wherein said hermeticallysealed container comprises a base sheet and a lid sheet, wherein thebase sheet and the lid sheet each comprise a flexible aluminum foiloptionally laminated with at least one plastic layer, and the lid sheetand base sheet are adhered to one another by heat sealing; or whereinsaid hermetically sealed container comprises a cavity formed from alaminate comprising a polyvinyl chloride base layer, an aluminum foillayer, and a polyamide layer, said laminate being hermetically sealed toan aluminum foil top layer; wherein administration of the dry powderdose is performed by inhalation from the dry powder inhaler, and saiddry powder inhaler provides a swirling airflow which distributes saiddry powder dose within the airflow produced by an inhalation effort by auser, and breaks up any aggregates present in the dry powder dose,wherein when the container is introduced into the dry powder inhaler,and when suction is applied through a mouthpiece of the inhaler, thesuction produces a swirling airflow which helps to distribute the powderof the dose effectively within the airflow and to reduce the extent towhich the powder is deposited on the inside of the mouthpiece, and saidairflow also assists to breakup any aggregates of the powder which maybe present in the dose, providing efficient entrainment of the powder inthe airflow with consequent efficient emptying of said blister.
 23. Themedical product according to claim 22, wherein said tiotropium powdercomprises the free ammonium cation of tiotropium and a counter-ionselected from the group consisting of chloride, bromide, iodide,methanesulfonate, p-toluenesulfonate or methyl sulfate.
 24. The medicalproduct according to claim 22, wherein said dry powder dose furthercomprises a lactose excipient.
 25. The medical product according toclaim 22, wherein the container forms a cavity molded from a plasticproviding hermetic properties.
 26. The medical product according toclaim 22, wherein said hermetically sealed container is part of the drypowder inhaler.
 27. The medical product according to claim 22, whereinsaid medical product is adapted for use in the treatment of arespiratory disorder.